The glycosaminoglycans are products of natural origin, obtained from tissues of animal origin, made by heterogeneous mixtures of chains of polysaccharides sulfated in different ways, having a very wide range of molecular weights, comprised from few thousands and some tens of thousands of Daltons.
Heparin is the most known among them, mainly made by units containing D-glucosamine and L-iduronic or D-glucuronic acid sulfated in different ways, having a range of molecular weights comprised between about 6,000 and 30,000 Daltons, generally used as an anticoagulant and antithrombotic drug in the form of sodium, potassium, calcium or magnesium salts.
Low molecular weight heparins, derivatives having a lesser degree of polymerization, with molecular weights comprised between about 1,500 and about 8,000 Daltons, having therapeutical characteristics like those of the heparin, are obtained by means of enzymatic or chemical treatment.
The chondroitins are other kinds of glycosaminoglycans extracted from tissues of animal origin, and one of them, previously known as chondroitin sulfate B, is the dermatan sulfate having antithrombotic and antihyperlipoproteinemic activity.
Low molecular weight fractions, between about 2,000 and about 8,000 Daltons, can also be obtained from dermatan sulfate like it happens for heparin.
The glucuronylglycosaminoglycan sulfate known under the name of sulodexide (International Non-proprietary Name), endowed with antithrombotic and antiatherosclerotic activity, is another substance pertaining to this class of drugs.
All these glycosaminoglycans were widely studied in the prevention and treatment of many pathologies of thrombotic and atherosclerotic origin, in the form of salts of alkali or alkali-earth metals like sodium, potassium, calcium or magnesium. However, their therapeutic use is hindered by the fact that these salts are mainly administered by parenteral way because of their scarce oral absorption.
For quite a time many remarkable efforts are carried out in order to fine adjuvant substances or derivatives or pharmaceutical formulations suitable for increasing their oral bioavailability, due to the great therapeutic interest that the glycosaminoglycans have in the prevention and treatment of the atherosclerotic and thrombotic pathologies.
At the beginning they tried to solve the problem by adding to aqueous solutions of heparin adjuvant substances like EDTA [Tidball et al., Proc. Soc. Exp. Biol. Med., 111, 713-5 (1962)], dimethylsulfoxide and diethylsulfone [Koh T. Y., Can. J. Biochem., 47, 951-4, (1969)], nitrilotriacetic acid [Jarret et al., Thromb. Diath. Haemorrh., 25, 187-200, (1971)] or citric acid [Sue T. K. et al, Can. J. Physiol. Pharmacol., 54, (4) 613-7, (1976)].
Engel R. H. and Riggi S. J. tried to help the oral absorption of the heparin by directly introducing emulsions made by aqueous solutions of heparin, a vegetable oil and ionic or non ionic surfactants into the duodenum of the experimental animals [J. Pharm. Sci., 58, 706-10 and 1372-5, (1969)].
Belgian patent BE 827,595 and British patent GB 1,563,161 describe the preparation of anhydrous suspensions of glycosaminoglycans in an oily medium in the presence of an anionic surfactant and show their absorption in the rat by intraduodenal administration.
Another way was the preparation of salts and complexes with weakly basic organic substances, like amines, or with amphoteric substances, like amides or aminoacids, as shown by U.S. Pat. Nos. 3,506,642 and 3,577,534.
More recently, they tried to help the absorption by using suitable pharmaceutical formulations based on liposomes as vehicles for the glycosaminoglycans [Masaharu Ueno et al., Chem. Pharm. Bull., 30, (6), 2245-78, (1982), Belgian patent BE 860,011, French patent FR 2,492,259] or by doing some complexes with quaternary ammonium bases [International publication PCT WO 85/05,362, U.S. Pat. Nos. 4,510,135 and 4,654,327].
Notwithstanding all these attempts, the need of finding new kinds of oral pharmaceutical formulations containing glycosaminoglycans endowed with better bioavailability, still exists.
The present invention constitutes a valid answer to this problem; in fact it was discovered that orally administrable pharmaceutical compositions, for instance tablets, capsules or sugar coated tablets, coated with an enterosoluble gastroresistant film, containing a lyophilisate made by a mixture of a glycosaminoglycan with a thickening substance and surfactants, after having unaltered crossed the gastric juices, disintegrated in the duodenum and intestine by releasing the glycosaminoglycan whose absorption is helped by the presence of the thickening substance and of the surfactants present in the lyophilisate, as shown by the tests of fibrinolytic activity carried out in man.